The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS) was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings showed that CEE + MPA had a negative impact on verbal memory (p < 0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo with no effect on other cognitive domains. In addition, these effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The findings from the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo show that CEE alone did not affect domain-specific cognitive function over time. Participants in the WHISCA and WHIMS studies continue to be followed through telephone cognitive assessments as they pass through the risk period for cognitive decline. The WHIMS Suite of Studies also included cognitive follow-up of women in the WHIMS-Younger (WHIMS-Y) study, who were randomized to hormone therapy through the WHI when aged 50-54 years. The WHIMS-Y study tested the hypothesis that hormone therapy around the time of the menopause may benefit cognitive function later in life. Initial results from the WHIMS-Y study were based on 1326 postmenopausal women studied with a validated telephone cognitive assessment battery an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years. The initial report included the first two administrations of the cognitive battery and showed neither harm nor benefit of early post-menopausal HT on later cognitive function. The WHIMS Suite of Studies is conducted by Wake Forest University, which is also the site for the Southeast Regional Center for WHI. Wake Forest Investigators lead the Aging, Cognition and Function interest group for the WHI. Follow-up cognitive evaluations continue through telephone assessments in the original WHIMS cohort (WHIMS extension study). The WHIMS-Y study has concluded as sufficient data were obtained in this cohort to test the study hypotheses. In addition to ongoing evaluations in the current WHIMS extension cohort, analysis of existing data continues. These analyses include genetic associations with risk for cognitive impairment and with cognitive trajectories, effects of particulate air pollution on cognitive, affective and brain outcomes, and determination of factors that promote cognitive resilience even in the presence of the APOE e4 genetic risk allele. In one recent paper, annual cognitive assessments from 2561 women, aged 75 to 92, were used to identify distinct trajectories, ranking women according to age-, race- and ethnicity-adjusted performance levels. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. Using this approach, women were grouped into five trajectories according to relative cognitive performance over time. These groups differed significantly according to 3 known risk factors for cognitive decline - education level, apolipoprotein E-e4 genotype, and type 2 diabetes mellitus -and a biomarker based on brain structure that has been linked to cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. Thus, longitudinal measures of an individual's relative performance on different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors. In a second paper, we used WHISCA data on positive affect (PA) and negative affect (NA) to determine whether affective state at baseline influenced risk of cognitive impairment (mild cognitive impairment (MCI) and probable dementia) in women without depression. Baseline PA and NA were assessed in 2137 postmenopausal women (mean age 73.8 years) who had participated in WHISCA and had received annual assessments with the Positive and Negative Affect Schedule (PANAS). Women were followed annually for an average of 11.3 years; those with elevated depressive symptoms at baseline were excluded. We found that higher NA was associated with a higher risk of MCI and probable dementia, even after adjusting for covariates including age, education, sociodemographic, lifestyle, and cardiovascular risk factors, global cognition, and HT assignment. PA was not significantly associated with either outcome. These results show that NA, even in the absence of elevated depressive symptoms, is associated with higher risk of MCI and dementia. The next phase of the WHIMS analyses are focusing on women who survive to old age (80+) and remain cognitively healthy, cognitive resilience. In addition, a new study is underway to evaluate the biology of cognitive resilience in women who carry the APOE e4 genetic risk allele for Alzheimer's disease but remain cognitively healthy in late life. Biospecimens obtained at WHI baseline will be used to conduct studies of insulin resistance, proteomics, metabolomics and auto-antibody profiles in APOE e4 escapees in comparison to those who develop cognitive impairment and in comparison to women with the APOE e3/e3 genotype.